Desmosomes are adhesive intercellular junctions that play critical roles in epidermal homeostasis by mediating robust cell-cell adhesion and by modulating signaling pathways that regulate epidermal differentiation. The importance of desmosomes is highlighted by numerous autoimmune and inherited skin diseases that compromise desmosome function and cause epidermal fragility. These diseases include pemphigus vulgaris (PV), a severe autoimmune epidermal blistering disease caused by autoantibodies (IgG) directed against the desmosomal cadherin desmoglein-3 (Dsg3), and severe dermatitis, multiple allergies and metabolic wasting (SAM) syndrome caused by DSG1 loss of function mutations. Our previous studies of PV revealed that desmosomal proteins are associated with lipid rafts, and our recent findings indicate that a mutation in the Dsg1TMD that abrogates lipid raft association, compromises desmosome formation, and causes SAM syndrome. Lipid rafts are important for a variety of cellular functions, including signaling, endocytosis and membrane domain formation. The important role of lipid rafts in regulating Dsg function in different skin diseases underscores the importance of Dsg association with lipid rafts in normal desmosome function and epidermal homeostasis. We hypothesize that Dsg association with rafts is required for desmosome assembly, segregation from adherens junctions, and for Dsg adhesive and signaling activities necessary for epidermal homeostasis. The experiments outlined in this proposal are designed to reveal the raft targeting features of desmosomal cadherins, how raft association regulates desmosome and adherens junction membrane domain formation, and how loss of Dsg raft association leads to SAM syndrome. The outcome of these studies will produce fundamentally new conceptual models for desmosome regulation and will form a foundation for the treatment of skin diseases associated with loss of desmosome function.